Abstract Head and neck squamous cell carcinoma (HNSCC) is a pervasive and dangerous disease with a 5-year survival rate of only 40-50%, demonstrating the need for improved therapeutics. The cancer stem cell (CSC) population in HNSCC has become an emerging area of study given its impact on treatment failure, metastasis, and its detrimental impact on patient survival. Therefore, the HNSCC CSC population is an essential target for new treatments. We revealed that the P53-related transcription factor ?Np63? is required for HNSCC CSC self-renewal, invasion, and migration. Preliminary data also reveals a strong transcriptional impact of ?Np63? on ELK3, uniquely in CSCs. ELK3 is an ETS-domain containing transcription factor involved in the hypoxia response. ELK3 has been observed to play a role in invasion, migration, and retention of stemness in certain cancer types; here, I propose that ?Np63?-driven ELK3 regulates these same properties in the HNSCC CSC population. In addition to uncovering this novel CSC signaling axis, I have also discovered KDM2A as an upstream regulator of the pathway. KDM2A is a lysine demethylase that primarily functions on histone H3K36me2 marks. Since this methylation mark is associated with an active chromatin conformation, KDM2A is typically studied as a repressor of target genes. I discovered HNSCC cells to be dependent on KDM2A for survival through a CRISPR screen targeting over 200 chromatin modulating proteins. In addition to this, I found that KDM2A regulates the expression of both ?Np63? and ELK3, as well as the HNSCC CSC phenotype these factors invoke. This novel finding opens the door to potential therapeutic intervention on a critical axis that maintains a poor differentiation state within the cancer. Thus, I will perform genetic rescues, ChIP-seq, and single cell RNA-seq experiments to better understand the mechanism of action behind KDM2A-?Np63?-ELK3 signaling. Furthermore, I will move my research in vivo to more accurately assess the practicality of targeting this pathway in tumors. This is unique work that will give me the opportunity to develop new technical skills like ChIP-seq, scRNA-seq, and tumor xenograft studies in mice. I will also continue my growth as a scientist through grant writing, attending Cold Spring Harbor Laboratory (CSHL) courses, student mentoring, reviewing manuscripts, and presenting my work in a number of formats at both CSHL and Stony Brook University, and also at outside scientific venues. Overall, this training opportunity will greatly enrich my graduate experience and prepare me for becoming a successful postdoc, thereby fostering my transition to independence.